A woman's exposure to estrogen represents her principal endocrine risk factor for developing endometriosis while exposure to progesterone during pregnancy represents a negative risk factor for this disease. However, recent evidence suggests that reduced endometrial sensitivity to progesterone may represent a potentially important element in the overall disease process. In an attempt to identify the consequences of reduced endometrial responsiveness to progesterone on the basic pathophysiology of endometriosis, we have focused on the failure of progesterone to down-regulate the expression of the matrix metalloproteinase (MMP) system during secretory maturation. The invasive events required for the establishment of ectopic endometrial growth involves the breakdown of extracellular matrix within the peritoneal cavity. The failure of progesteone to down-regulate endometrial expression of key MMPs in endometriosis patients increases the invasive capacity of their tissue in a chimeric human/nude mouse model of endometriosis. We hypothesize that, in women with endometriosis, reduced progesterone responsiveness compromises cell-cell communication during secretory maturation within the eutopic endometrium. Reduced progesterone responsiveness specifically disrupts the expression of key transforming growth factor-p (TGF-P) signaling proteins leading to an epithelial-dominant pattern of cell-cell communication. Epithelialdominant cell-cell communication acts to increase MMP expression and promote the ability of endometrial fragments to rapidly invade the peritoneal surface, acquire a vasculature and establish the disease endometriosis. To test our hypothesis, we propose three Specific Aims: 1) to determine whether disruption of PR isotype expression in stromal cells and/or TGF-(3 signaling is linked to .the failure of progesterone to down-regulate MMP-3 and MMP-7 expression in the eutopic endometium of women with endometriosis and to determine if surgical reduction of ectopic disease with or without progesterone therapy restores normal MMP regulation 2) to determine whether reduced progesterone sensitivity in the endometrium of women with endometriosis negatively affects the synthesis of retinoic acid during stromal decidualization 3) to determine the functional impact of epithelial-dominant cell-cell communication in vitro and during the invasive establishment of experimental endometriosis in vivo.